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PubMedDate not supplied

Nucleic acid labeling with [3H]orotic acid and nucleotide profile in rats in protein deprivation, enteral and parenteral essential amino acid administration, and 5-fluorouracil treatment.

Rats were fed a 0% casein diet for 1 week, with or without enteral or parenteral administration of essential amino acids, or a 25% casein diet, in one group supplemented with 5-fluorouracil treatment. Ninety minutes before sacrifice the rats were given a tracer of [3H]orotic acid. Incorporation into the acid soluble fraction, RNA, and DNA was determined in liver, small intestine, bone marrow, and kidney. Nucleotide profile was examined in liver and intestine. Protein deficiency caused inter alia a decrease in body weight; a decrease in RNA/DNA ratio and an increase in the specific RNA labeling in liver and kidney; an altered nucleotide profile in the liver; an increase in the nucleotide/DNA and RNA/DNA ratios and a decrease in the specific labeling of the acid soluble fraction, RNA, and DNA in the bone marrow. These changes were prevented to the same extent by giving essential amino acids, either orally or intravenously. The minor changes in intestinal nucleotide profile in protein deprivation were prevented to a slightly larger extent by amino acids orally than parenterally. 5-Fluorouracil treatment gave a decrease in the RNA/DNA ratio in the liver and kidney but an increase in the nucleotide/DNA and RNA/DNA ratios in the bone marrow. Nucleotide profiles were unaltered. The amount of DNA per gram of tissue decreased in bone marrow and increased in kidney. Parenteral administration per se resulted in almost no changes.

Amino Acids↗
PubMed1981

Effect of amino acid concentration on orotic acid production by bovine mammary tissue.

Investigations were to determine if bovine mammary tissue could synthesize orotate and to assess the influence of amino acids on production of orotate. Mammary tissue from 6 Holstein cows was obtained immediately after slaughter. Tissue slices were incubated in either a modified Krebs-Ringer bicarbonate buffer, the same medium containing a physiological concentration of amino acids, or a third medium containing a fourfold concentration of the amino acid mixture. In all experiments, tissue slices were preincubated in the physiological amino acid medium for 5, 10, and 15 min (30 total min) with fresh medium changes after each incubation with one of the three treatment media for three consecutive 20-min periods. Tissue slices incubated in the physiological amino acid medium for a total of 90 min synthesized 28.5 microgram orotate/g wet tissue after correction for the initial tissue contribution. Orotate secreted by the tissue slices increased as concentration of amino acids increased. Lactose released into the medium was not affected by amino acid concentration. Bovine mammary tissue can synthesize substantial amounts of orotate, and tissue synthesis of orotate but not lactose increased as amino acid concentration increased.

Amino Acids↗
PubMed2004

Analytical derivatization-a tool for determination of orotic acid.

Derivatization of orotic acid (OA) into various forms (trimethylsilylderivate, alkyl ester and per-methylated derivate) and their evaluation by GC/MS is described. The tested approach includes ion-exchange SPE clean-up, evaporation and chemical reaction with different types of derivatization agents (N,O-bis-(trimethylsilyl)trifluoroacetamide with trimethylchlorosilane, butanol with acetylchloride and ethereal solution of diazomethane). Derivate originated in the reaction with diazomethane was used for determination of urinary orotic acid by GC/MS. Detection limit of 0.28 micromol l(-1) was reached using the ion 82 m/z in single ion monitoring (SIM) mode. Linearity of the method was tested within the range of 3.4-2503.4 micromol l(-1) covering physiological and pathological levels of orotic acid in urine sample. Recoveries were within the range 93.7-110.6%. Application of the method on the patient with defect of ornithine transcarbamylase (OTC) was demonstrated as well.

Chromatography, Liquid↗
PubMed1992

Nitrogen-stimulated orotic acid synthesis and nucleotide imbalance.

Orotic acid, first discovered in ruminant milk, is an intermediate in the pyrimidine biosynthesis pathway of animal cells. Its synthesis is initiated by the formation of carbamoyl phosphate (CP) in the cytoplasm, with ammonia derived from glutamine. Ureotelic species also form CP in the first step of urea synthesis in liver mitochondria. For that, ammonia is derived from tissue fluid. When there is insufficient capacity for detoxifying the load of ammonia presented for urea synthesis, CP leaves the mitochondria and enters the pyrimidine pathway, where orotic acid biosynthesis is stimulated, orotic acid excretion in urine then increases. Orotic acid synthesis is abnormally high with hereditary deficiencies of urea-cycle enzymes or uridine monophosphate synthase. It is also elevated by ammonia intoxication and during feeding of diets high in protein, high in lysine with respect to arginine, or deficient in arginine, ornithine, and citrulline. Rats fed 1% orotic acid or diets deficient in urea-cycle amino acids develop fatty livers, which has not been demonstrated in other species. Humans consuming 6 g of orotic acid daily have not shown adverse effects. Rats fed 1% orotic acid or arginine-deficient diets also showed more and larger foci positive for gamma-glutamyl transpeptidase and more liver tumors after administration of carcinogens and partial hepatectomy. Orotic acid feeding was also associated with the tendency for development of larger mammary tumors induced by chemical carcinogens in rats and with development of urinary bladder calculi containing high concentrations of orotic acid in mice. Conditions that raise tissue orotic acid change purine-pyrimidine ratios. It is unknown whether tissue orotate concentrations play a role in the recently observed enhanced proliferation of cells in the colon of rats fed high-protein, high-fat diets or in the promotion of chemically induced colon cancer by intrarectal administration of ammonium acetate.

Ammonia↗
PubMed1980

Conditions affecting the colorimetry of orotic acid and orotidine in urine.

We studied conditions affecting a colorimetric assay of total orotic acid (orotic acid plus orotidine) in urine. Most interfering substances can be conveniently removed on a small column of cation-exchange resin, and an improved control reaction corrects for residual background color. Analytical recovery from urine is nearly complete (greater than 95%) and the absorption spectrum for analyte eluted from the column closely resembles that for an orotic acid standard. We determined reference intervals for total orotic acid, expressed as a molar ratio to creatinine, for neonates, children, and adults, and assessed the effect of age, protein intake, and pregnancy. The method is simple enough to use as a reliable and accurate urine-screening test.

Adult↗
PubMed1989

Sensitivity of the recently infarcted heart to cardioplegic arrest. Beneficial effect of pretreatment with orotic acid.

The mortality and morbidity of cardiac operations are increased in the presence of an established, recent myocardial infarct. To help understand the mechanisms for this and to develop a therapeutic strategy, we studied the response of the recently infarcted canine heart to hypothermic cardioplegia and the effect of pretreatment with orotic acid. Orotic acid is a precursor of nucleic acids with the ability to enhance protein synthesis. In 21 greyhound dogs, a myocardial infarct was produced by ligation of the left anterior descending coronary artery. Ten of these then received oral orotic acid (100 mg/kg/day) for 4 days and 11 were untreated. A sham group of eight dogs had a thoracotomy only and therefore had normal hearts (normal group). Four days later, all dogs underwent 60 minutes of cardioplegic arrest at 28 degrees C. Before arrest, stroke work index was lower and myocardial oxygen consumption at comparable work levels was higher in both the orotic acid and untreated infarct groups than in the normal group. After arrest and reperfusion, there was a severe depression of ventricular function in the untreated infarct group, with only 18% recovery of prearrest stroke work. In the orotic acid infarct group, recovery of prearrest function (43%) was similar to that in the normal group (56%) and significantly greater than in the untreated infarct group (p less than 0.01). After reperfusion, the untreated infarct group had a lower oxygen consumption, lower myocardial levels of adenosine triphosphate and glycogen, and higher lactate and water contents than before arrest (all p less than 0.05). In the orotic acid and normal groups, these variables returned to prearrest levels. We conclude that an established, recent myocardial infarct places the noninfarcted myocardium under stress and increases its sensitivity to hypothermic cardioplegia. This sensitivity is markedly reduced by treatment with orotic acid.

Animals↗
PubMed1980

Orotic acid content of infant formulas.

The orotic acid content of four commercially available infant formulas has been examined. Enfamil contains 118 microgram orotic acid per milliliter as fed, Similac 98, SMA 27, and Isomil less than 1 microgram/ml. As expressed relative to total solids, these formulas contain less than 0.1% orotic acid. Since consumption of 1% orotic acid does not lead to a fatty liver in any species examined other than the rat and 0.1% orotic acid fails to induce statistically significant hepatic changes in the rat, it is suggested that orotic acid at the level found in these formulas is not likely to pose a health hazard to the infants consuming them.

Infant Food↗
PubMed1999

Effects of dietary protein type on the response of lipid metabolism to orotic acid in rats.

The effects of orotic acid supplementation to casein, egg protein, soy protein and wheat gluten diets on the lipids of liver and serum were compared. When orotic acid was added, the contents of total lipids and triacylglycerol in the liver of the casein group were significantly higher or tended to be higher than those of the other three dietary groups. Dietary orotic acid had no effect on the food intake. The liver weight, and liver total lipids, triacylglycerol, cholesterol and phospholipids were increased or tended to be increased by the addition of orotic acid. The serum triacylglycerol level was decreased by the addition of orotic acid to either the casein or soy protein diet. Thus, the response to liver lipid accumulation induced by orotic acid feeding depended on the dietary protein type.

Animals↗
PubMed1984

Hypocholesteremia induced by orotic acid: dietary effects and species specificity.

Effects of 1% dietary orotic acid on lipid metabolism were examined in rats, mice, hamsters and guinea pigs. The influences of diet composition, age and sex on alterations induced by orotic acid were also studied. Hypocholesteremia and hepatic steatosis developed in rats fed orotic acid. These responses were little affected by dietary changes in lipid (0, 2 or 5% corn oil) or carbohydrate (high sucrose, high starch or high fiber). When included in diets containing cholesterol and cholic acid, orotic acid prevented a rise in serum cholesterol but did not maintain a normal ratio of HDL to total cholesterol. The responses of mice to orotic acid were opposite to those of rats; liver lipid was decreased, and serum cholesterol was increased. Hamsters and guinea pigs were unaffected by the compound. Thus, orotic acid is hypocholesteremic in rats, hypercholesteremic in mice and normocholesteremic in hamsters and guinea pigs. Age did not alter responses of rats to 1% dietary orotic acid. In rats and mice, sex influenced changes in hepatic lipid, with females more responsive than males.

Aging↗
PubMed1985

Assessment in humans of hypolipidemia induced by orotic acid.

The hypolipidemia induced by oral orotic acid in rats but not in other experimental species was investigated in human adults. Twelve outpatients in a medically-supervised weight reduction program participated in the study. After adaptation to their restricted dietary regime for at least 8 weeks, all subjects were given placebos (1 g lactose/day) for 2 weeks, then orotic acid (1 g/day) for 4 weeks, followed by placebos for 2 more weeks. Pertinent dietary, urinary, and serum parameters were monitored biweekly and intake of calories, carbohydrate, protein and fat was similar throughout. The ingestion of orotic acid did not lower serum triglycerides or cholesterol in these subjects. Since the daily dose tested corresponds to the orotic acid in 12 liters of cow's milk, milk orotic acid at levels normally consumed should not be considered a hypolipidemic or hypocholesteremic agent for humans.

Adult↗